The long-term goal of this project is to elucidate the deregulated survival signaling pathways critical for prostate cancer development and progression. Several recent studies demonstrated that a reciprocal regulation of the two major survival signaling pathways driven by PI3K-AKT and the androgen receptor (AR) in prostate cancer cells plays an important role in castration resistance. Simultaneous inhibition of both pathways has a more superior efficacy in attenuating tumor growth in preclinical models. Therefore, fully understanding the mechanisms by which these two survival pathways are regulated in prostate cancer will provide molecular basis for development of new effective therapy. We have recently identified the ubiquitin E3 ligase RNF6, which is overexpressed in castration- resistant prostate cancer, as a co-factor of AR. Inhibition of RNF6 expression compromises AR transcriptional activity and attenuates tumor growth under androgen-depleted conditions, indicating an important role of RNF6 in prostate progression. To further understand the role of RNF6 in prostate, we have generated a mouse model with targeted disruption in the Rnf6 locus. Rnf6-deficient mice are defective in prostate development, which is accompanied with compromised multiple signaling pathways, including AR and Akt pathways. We showed that the expression of several AR-targeting microRNAs is up-regulated in Rnf6-deficient prostates, concomitant with a reduction of AR protein level. In addition, we have identified RNF6 as a potential new regulator of AKT activation. We hypothesize that RNF6 may function as a key regulator of multiple survival signaling pathways critical for prostate cancer progression via modulating the activity of both AR and AKT, and inactivation of RNF6 may effectively attenuate the growth of castration-resistant prostate tumors by inhibiting both AR and AKT- mediated survival signaling. Three specific aims are proposed: Aim 1) Delineate the mechanisms by which RNF6 modulates AR expression in prostate cancer cells; Aim 2) Investigate the mechanisms by which RNF6 modulates AKT activity; Aim 3) Examine the effects of inactivation of Rnf6 and its downstream effectors on castration-resistant prostate cancer in preclinical models.